DOCSLIB.ORG

Breast Cancer Genome-Wide Association Studies: There Is Strength in Numbers

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Breast Cancer Genome-Wide Association Studies: There Is Strength in Numbers Oncogene (2012) 31, 2121–2128 & 2012 Macmillan Publishers Limited All rights reserved 0950-9232/12 www.nature.com/onc REVIEW Breast cancer genome-wide association studies: there is strength in numbers D Fanale1,3, V Amodeo1,3, LR Corsini1,3, S Rizzo1, V Bazan1,2 and A Russo1,2 1Department of Surgical and Oncological Sciences, Section of Medical Oncology, University of Palermo, Palermo, Italy and 2Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA, USA Breast cancer (BC) is a heterogeneous disease that Introduction exhibits familial aggregation. Family linkage studies have identified high-penetrance genes, BRCA1, BRCA2, Breast cancer (BC) is the most common cancer and the PTEN and TP53, that are responsible for inherited BC second leading cause of cancer death among women syndromes. Moreover, a combination of family-based and (Parkin et al., 2005). population-based approaches indicated that genes involved The family history is the main risk factor for BC, in DNA repair, such as CHEK2, ATM, BRIP and indicating that the genetic factors are very important in the PALB2, are associated with moderate risk. Therefore, all development of disease (Antoniou and Easton, 2006). of these known genes account for only 25% of the familial In the 1990s, linkage studies in multiple case families have aggregation cases. Recently, genome wide association identified two major susceptibility genes in BC BRCA1 and studies (GWAS) in BC revealed single nucleotide poly- BRCA2 (Miki et al., 1994; Wooster et al., 1995). morphisms (SNPs) in five novel genes associated to Germline mutations in BRCA1 and BRCA2 genes susceptibility: TNRC9, FGFR2, MAP3K1, H19 and occur rarely in the general population but confer high lymphocyte-specific protein 1 (LSP1). The most strongly risks of breast and ovarian cancer and a lower risk for associated SNP was in intron 2 of the FGFR2 gene that is other cancers (Antoniou et al., 2003; Thompson and amplified and overexpressed in 5–10% of BC. rs3803662 Easton, 2004). of TNRC9 gene has been shown to be the SNP with the TP53 and PTEN mutations are also present in the strongest association with BC, in particular, this poly- population at low frequency and lead to very high BC morphism seems to be correlated with bone metastases risk associated with rare cancer syndrome, however, and estrogen receptor positivity. Relevant data indicate population-based studies have estimated that alterations that SNP rs889312 in MAP3K1 is correlated with BC in these genes account only the 15% of the familial risk susceptibility only in BRCA2 mutation carriers, but is not of BC (Sidransky et al., 1992; FitzGerald et al., 1998; associated with an increased risk in BRCA1 carriers. Peto et al., 1999; Dite et al., 2003). Finally, different SNPs in LSP1 and H19 and in minor Further, genetic linkage analyses failed to identify genes probably were associated with BC risk. New additional high-penetrance susceptibility genes and the susceptibility allelic variants associated with BC risk were identification of rare variants of genes involved in DNA recently discovered including potential causative genes repair, such as CHEK2, ATM, BRIP and PALB2 in involved in regulation of cell cycle, apoptosis, metabolism families lacking BRCA mutations (Meijers-Heijboer and mitochondrial functions. In conclusion, the identifica- et al., 2002; Thompson et al., 2005; Rahman et al., tion of disease susceptibility loci may lead to a better 2007; Hollestelle et al., 2010), associated with a understanding of the biological mechanism for BC to moderate risk of disease, can explain only a small improve prevention, early detection and treatment. portion of familial risk. Oncogene (2012) 31, 2121–2128; doi:10.1038/onc.2011.408; Therefore, all of these known genes account for only published online 26 September 2011 25% of the familial aggregation cases (Thompson and Easton, 2004), suggesting that most of the familial risk Keywords: FGFR2; GWAS; H19; LSP1; MAP3K1; of BC can plausibly involve a combination of multiple TNRC9 low-penetrance susceptibility alleles, each conferring a small effect on BC risk (Antoniou and Easton, 2006; Table 1). According to this model defined ‘polygenic’, proposed to explain the genetic susceptibility to BC, a large number of low-risk variants occurs with high frequency Correspondence: Professor A Russo, Department of Surgical and in populations, therefore, it may have a multiplicative Oncological Sciences, Section of Medical Oncology, Universita` di effect in determining the overall risk of disease (Pharoah Palermo, via del Vespro 129, 90127 Palermo, Italy. et al., 2002; Figure 1). A significant part of polygenic E-mail: [email protected] 3These authors contributed equally to this work contribute to low-penetrance susceptibility may rise by Received 10 July 2011; revised 9 August 2011; accepted 9 August 2011; non-conservative missense mutations in evolutionarily published online 26 September 2011 conserved domains. GWAS in breast cancer D Fanale et al 2122 Table 1 Genetic loci implicated in breast cancer susceptibility population the identification of a susceptibility allele with a frequency of 5% requires over 800 cases. In the High penetrance, Low penetrance, Low penetrance, low frequency low frequency high frequency same population, the identification of a susceptibility allele with a frequency of 1% requires over 3700 BRCA1 CHEK2 FGFR2 unselected cases, whereas about 700 would be enough BRCA2 ATM TNRC9 if three affected families are selected. Therefore, the p53 PALB2 LSP1 PTEN BRIP1 MAP3K1 power of association studies can be significantly SLC4A7 increased using selected cases with a family history of COX11 cancer because less cases are required to demonstrate the association with disease (Houlston and Peto, 2004). The potential of the association studies of cases with a family history to identify low-penetrance alleles confer- ring a relative risk of 2 has been demonstrated by the mutation CHEK2 1100delC in patients with BC. This variant carried by 1% of the population confers an increased risk of 1.7-fold. The frequency was not significantly increased in unselected cases (1.4%), but it was strongly increased in familial cases without BRCA1 and BRCA2 mutations (5.1%; Meijers-Heijboer et al., 2002). In the past years several novel risk alleles for BC were identified by four recent GWA studies: Breast Cancer Association Consortium, Cancer Genetic Markers of Susceptibility, DeCode Islanda, Memorial Sloan–Ket- tering Cancer Center (Easton et al., 2007; Hunter et al., 2007; Gold et al., 2008; Stacey et al., 2008). In each of them the association study was shared into Figure 1 Allelic variants at low frequency tend to be associated with higher relative risk of BC (for example, BRCA1, BRCA2), three phases: the first phase identifies the common SNPs high-frequency allelic variants are associated with lower RR in cases and controls, the second phase evaluates how (for example, FGFR2, LSP1, and so on) configuring an inverse many of the above SNPs are common to a greater correlation. number of cases and controls and, finally, the third phase aims to identify new alleles of susceptibility of BC. Easton et al., in their study, identified five indepen- Genome-wide association studies (GWAS) dent loci associated with increased susceptibility to BC (Po10À7). This multistage study involved in the first In recent years the research of low-penetrance allelic stage 390 BC cases with a strong family history and variants was conducted mainly through GWAS. These 364 controls, and 3990 cases and 3916 controls in the studies use a large number of common genetic single second stage. nucleotide polymorphisms (SNPs) to identify associa- To define the risk associated with the 30 most tions with disease that rely upon patterns of linkage significant SNPs, a third stage of the study was disequilibrium (LD) in the human genome (Hirshfield conducted involving 21 860 cases and 22 578 controls et al., 2010). The power of GWAS is to evaluate the from 22 additional studies in the Breast Cancer association of genetic variants at different loci on Association Consortium. different chromosomes (LD) in large series of cases These combined analyses allowed to observe that the versus controls, analyzing a panel of hundred thousand SNPs showing a stronger statistical evidence of associa- SNPs simultaneously, to identify new alleles of suscept- tion with an increased familial risk were: rs2981582 lies ibility to BC (Orr and Chanock, 2008). In the human in intron 2 of FGFR2, rs12443621 and rs8051542 within genome has been estimated that there are seven million TNRC9, rs889312 lies in a region that contain MAP3K1 of common SNPs that have a minor allele frequency gene, rs3817198 lies in intron 10 of lymphocyte-specific (m.a.f.), 45% and because recombination occurs in protein 1 (LSP1) and rs2107425 within the H19 gene. different hot-spots, the nascent polymorphisms are often Unlike other BC susceptibility genes previously strongly correlated. identified that are involved in DNA repair and sex These studies therefore provide a powerful tool to hormone synthesis, in this work three of the five loci identify novel markers for susceptibility and prognosis reported contain genes involved in regulation of cell of disease (Peto, 2002; Houlston and Peto, 2004; Easton growth and cell signaling (Easton et al., 2007). and Eeles, 2008). In the GWA studies the accumulation Starting from this study of Easton et al., in attempt of a large number of data is crucial. Houlston and Peto, to identify further loci associated with BC risk, (2004) have estimated the number of cases required to Ahmed et al. have genotyped in a third stage further identify low-penetrance alleles conferring a relative risk 814 SNPs, involving 3878 cases and 3928 controls from of two both in an unselected population and in families three studies of the Cancer Genetic Markers of with first-degree relatives affected. In an unselected Susceptibility.
Load more

Recommended publications
  • Aberrant Methylation Underlies Insulin Gene Expression in Human Insulinoma
    ARTICLE https://doi.org/10.1038/s41467-020-18839-1 OPEN Aberrant methylation underlies insulin gene expression in human insulinoma Esra Karakose1,6, Huan Wang 2,6, William Inabnet1, Rajesh V. Thakker 3, Steven Libutti4, Gustavo Fernandez-Ranvier 1, Hyunsuk Suh1, Mark Stevenson 3, Yayoi Kinoshita1, Michael Donovan1, Yevgeniy Antipin1,2, Yan Li5, Xiaoxiao Liu 5, Fulai Jin 5, Peng Wang 1, Andrew Uzilov 1,2, ✉ Carmen Argmann 1, Eric E. Schadt 1,2, Andrew F. Stewart 1,7 , Donald K. Scott 1,7 & Luca Lambertini 1,6 1234567890():,; Human insulinomas are rare, benign, slowly proliferating, insulin-producing beta cell tumors that provide a molecular “recipe” or “roadmap” for pathways that control human beta cell regeneration. An earlier study revealed abnormal methylation in the imprinted p15.5-p15.4 region of chromosome 11, known to be abnormally methylated in another disorder of expanded beta cell mass and function: the focal variant of congenital hyperinsulinism. Here, we compare deep DNA methylome sequencing on 19 human insulinomas, and five sets of normal beta cells. We find a remarkably consistent, abnormal methylation pattern in insu- linomas. The findings suggest that abnormal insulin (INS) promoter methylation and altered transcription factor expression create alternative drivers of INS expression, replacing cano- nical PDX1-driven beta cell specification with a pathological, looping, distal enhancer-based form of transcriptional regulation. Finally, NFaT transcription factors, rather than the cano- nical PDX1 enhancer complex, are predicted to drive INS transactivation. 1 From the Diabetes Obesity and Metabolism Institute, The Department of Surgery, The Department of Pathology, The Department of Genetics and Genomics Sciences and The Institute for Genomics and Multiscale Biology, The Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
    [Show full text]
  • Analysis of Gene Expression Data for Gene Ontology
    ANALYSIS OF GENE EXPRESSION DATA FOR GENE ONTOLOGY BASED PROTEIN FUNCTION PREDICTION A Thesis Presented to The Graduate Faculty of The University of Akron In Partial Fulfillment of the Requirements for the Degree Master of Science Robert Daniel Macholan May 2011 ANALYSIS OF GENE EXPRESSION DATA FOR GENE ONTOLOGY BASED PROTEIN FUNCTION PREDICTION Robert Daniel Macholan Thesis Approved: Accepted: _______________________________ _______________________________ Advisor Department Chair Dr. Zhong-Hui Duan Dr. Chien-Chung Chan _______________________________ _______________________________ Committee Member Dean of the College Dr. Chien-Chung Chan Dr. Chand K. Midha _______________________________ _______________________________ Committee Member Dean of the Graduate School Dr. Yingcai Xiao Dr. George R. Newkome _______________________________ Date ii ABSTRACT A tremendous increase in genomic data has encouraged biologists to turn to bioinformatics in order to assist in its interpretation and processing. One of the present challenges that need to be overcome in order to understand this data more completely is the development of a reliable method to accurately predict the function of a protein from its genomic information. This study focuses on developing an effective algorithm for protein function prediction. The algorithm is based on proteins that have similar expression patterns. The similarity of the expression data is determined using a novel measure, the slope matrix. The slope matrix introduces a normalized method for the comparison of expression levels throughout a proteome. The algorithm is tested using real microarray gene expression data. Their functions are characterized using gene ontology annotations. The results of the case study indicate the protein function prediction algorithm developed is comparable to the prediction algorithms that are based on the annotations of homologous proteins.
    [Show full text]
  • Original Article Correlation Between LSP1 Polymorphisms and the Susceptibility to Breast Cancer
    Int J Clin Exp Pathol 2015;8(5):5798-5802 www.ijcep.com /ISSN:1936-2625/IJCEP0005835 Original Article Correlation between LSP1 polymorphisms and the susceptibility to breast cancer Hai Chen, Xiaodong Qi, Ping Qiu, Jiali Zhao Department of Galactophore, The General Hospital of Beijing Military Command, Beijing, China Received January 12, 2015; Accepted March 16, 2015; Epub May 1, 2015; Published May 15, 2015 Abstract: Objective: The present study aimed at assessing the relationship between Leukocyte-specific protein 1 gene (LSP1) polymorphisms (rs569550 and rs592373) and the pathogenesis of breast cancer (BC). Methods: 70 BC patients and 72 healthy subjects were enrolled in the study. Rs569550 and rs592373 polymorphisms were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Odds ratio (OR) with 95% confidence interval (CI) were calculated by the chi-squared test to assess the relationship between LSP1 polymorphisms and BC risk. Linkage disequilibrium (LD) and haplotypes were also analyzed by HaploView software. Results: Genotype distribution of the control was in accordance with Hardy-Weinberg equilibrium (HWE). The homo- zygous genotype TT and T allele of rs569550 could significantly increase the risk of BC (TT vs. GG: OR=3.17, 95% CI=1.23-8.91; T vs. G: OR=1.63, 95% CI=1.01-2.64). For rs592373, mutation homozygous genotype CC and C allele were significantly associated with BC susceptibility (CC vs. TT: OR=4.45, 95% CI=1.38-14.8; C vs. T: OR=1.70, 95% CI=1.03-2.81). LD and haplotypes analysis of rs569550 and rs592373 polymorphisms showed that T-C haplotype was a risk factor for BC (T-C vs.
    [Show full text]
  • Meta-Analysis of Nasopharyngeal Carcinoma
    BMC Genomics BioMed Central Research article Open Access Meta-analysis of nasopharyngeal carcinoma microarray data explores mechanism of EBV-regulated neoplastic transformation Xia Chen†1,2, Shuang Liang†1, WenLing Zheng1,3, ZhiJun Liao1, Tao Shang1 and WenLi Ma*1 Address: 1Institute of Genetic Engineering, Southern Medical University, Guangzhou, PR China, 2Xiangya Pingkuang associated hospital, Pingxiang, Jiangxi, PR China and 3Southern Genomics Research Center, Guangzhou, Guangdong, PR China Email: Xia Chen - [email protected]; Shuang Liang - [email protected]; WenLing Zheng - [email protected]; ZhiJun Liao - [email protected]; Tao Shang - [email protected]; WenLi Ma* - [email protected] * Corresponding author †Equal contributors Published: 7 July 2008 Received: 16 February 2008 Accepted: 7 July 2008 BMC Genomics 2008, 9:322 doi:10.1186/1471-2164-9-322 This article is available from: http://www.biomedcentral.com/1471-2164/9/322 © 2008 Chen et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Background: Epstein-Barr virus (EBV) presumably plays an important role in the pathogenesis of nasopharyngeal carcinoma (NPC), but the molecular mechanism of EBV-dependent neoplastic transformation is not well understood. The combination of bioinformatics with evidences from biological experiments paved a new way to gain more insights into the molecular mechanism of cancer. Results: We profiled gene expression using a meta-analysis approach. Two sets of meta-genes were obtained. Meta-A genes were identified by finding those commonly activated/deactivated upon EBV infection/reactivation.
    [Show full text]
  • LSP1-Myosin1e Bi-Molecular Complex Regulates Focal Adhesion Dynamics
    bioRxiv preprint doi: https://doi.org/10.1101/2020.02.26.963991; this version posted February 27, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. LSP1-myosin1e bi-molecular complex regulates focal adhesion dynamics and cell migration Katja Schäringer1*, Sebastian Maxeiner1*, Carmen Schalla1, Stephan Rütten2, Martin Zenke1 and Antonio Sechi1 1Institute of Biomedical Engineering, Dept. of Cell Biology, RWTH Aachen University, Pauwelsstrasse, 30, D-52074 Aachen, Germany 2Electron Microscopy Facility, Institute of Pathology, RWTH Aachen University, Pauwelsstrasse, 30, D-52074 Aachen, Germany *equal contribution Corresponding author: Email: [email protected] Telephone: +49 241 8085248 Running head: LSP1-myosin1e complex regulates cell migration. Keywords: Actin cytoskeleton remodelling, focal adhesions, cell motility, macrophages. 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.02.26.963991; this version posted February 27, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Abstract Several cytoskeleton-associated proteins and signalling pathways work in concert to regulate actin cytoskeleton remodelling, cell adhesion and migration. We have recently demonstrated that the bi-molecular complex between the leukocyte-specific protein 1 (LSP1) and myosin1e controls actin cytoskeleton remodelling during phagocytosis. In this study, we show that LSP1 down regulation severely impairs cell migration, lamellipodia formation and focal adhesion dynamics in macrophages. Inhibition of the interaction between LSP1 and myosin1e also impairs these processes resulting in poorly motile cells, which are characterised by few and small lamellipodia.
    [Show full text]
  • Anti-LSP1 Antibody (ARG55377)
    Product datasheet [email protected] ARG55377 Package: 50 μl anti-LSP1 antibody Store at: -20°C Summary Product Description Rabbit Polyclonal antibody recognizes LSP1 Tested Reactivity Hu Tested Application WB Host Rabbit Clonality Polyclonal Isotype IgG Target Name LSP1 Antigen Species Human Immunogen Synthetic peptide corresponding to aa. 121-149 of Human LSP1. Conjugation Un-conjugated Alternate Names Lymphocyte-specific protein 1; pp52; 52 kDa phosphoprotein; 47 kDa actin-binding protein; WP34; Lymphocyte-specific antigen WP34 Application Instructions Application table Application Dilution WB 1:1000 Application Note * The dilutions indicate recommended starting dilutions and the optimal dilutions or concentrations should be determined by the scientist. Positive Control Daudi Calculated Mw 37 kDa Properties Form Liquid Purification Affinity purification with immunogen. Buffer PBS (without Mg2+ and Ca2+, pH 7.4), 150mM NaCl, 0.02% Sodium azide and 50% Glycerol Preservative 0.02% Sodium azide Stabilizer 50% Glycerol Storage instruction For continuous use, store undiluted antibody at 2-8°C for up to a week. For long-term storage, aliquot and store at -20°C. Storage in frost free freezers is not recommended. Avoid repeated freeze/thaw cycles. Suggest spin the vial prior to opening. The antibody solution should be gently mixed before use. Note For laboratory research only, not for drug, diagnostic or other use. www.arigobio.com 1/2 Bioinformation Database links GeneID: 4046 Human Swiss-port # P33241 Human Gene Symbol LSP1 Gene Full Name lymphocyte-specific protein 1 Background This gene encodes an intracellular F-actin binding protein. The protein is expressed in lymphocytes, neutrophils, macrophages, and endothelium and may regulate neutrophil motility, adhesion to fibrinogen matrix proteins, and transendothelial migration.
    [Show full text]
  • Expression of Mouse LSP1/S37 Isoforms S37 Is Expressed in Embryonic Mesenchymal Cells
    Journal of Cell Science 107, 3591-3600 (1994) 3591 Printed in Great Britain © The Company of Biologists Limited 1994 Expression of mouse LSP1/S37 isoforms S37 is expressed in embryonic mesenchymal cells V. L. Misener1, C.-c. Hui2, I. A. Malapitan1, M.-E. Ittel1, A. L. Joyner2,3 and J. Jongstra1,* 1The Arthritis Centre-Research Unit, The Toronto Hospital Research Institute and Department of Immunology, University of Toronto, Toronto, Ontario, Canada 2Division of Molecular and Developmental Biology, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada 3Department of Molecular and Medical Genetics, University of Toronto, Toronto, Ontario, Canada *Author for correspondence at: Toronto Western Hospital, Room 13-419, 399 Bathurst Street, Toronto, Ontario, M5T 2S8 Canada SUMMARY Mouse LSP1 is a 330 amino acid intracellular F-actin 18 bp encoding the 6 amino acids HLIRHQ of the acidic binding protein expressed in lymphocytes and domain. Therefore, the Lsp1 gene encodes four protein macrophages but not in non-hematopoietic tissues. A 328 isoforms: full-length LSP1 and S37 proteins, designated amino acid LSP1-related protein, designated S37, is LSP1-I and S37-I and the same proteins without the expressed in murine bone marrow stromal cells, in fibro- HLIRHQ sequence, designated LSP1-II and S37-II. By in blasts, and in a myocyte cell line. The two proteins differ situ hybridization analysis we show that the S37 isoforms only at their N termini, the first 23 amino acid residues of are expressed in mesenchymal tissue, but not in adjacent LSP1 being replaced by 21 different residues in S37. The epithelial tissue, of several developing organs during mouse presence of different amino termini suggests that the LSP1 embryogenesis.
    [Show full text]
  • Integrative Differential Expression and Gene Set Enrichment Analysis Using Summary Statistics for Scrna-Seq Studies
    ARTICLE https://doi.org/10.1038/s41467-020-15298-6 OPEN Integrative differential expression and gene set enrichment analysis using summary statistics for scRNA-seq studies ✉ Ying Ma 1,7, Shiquan Sun 1,7, Xuequn Shang2, Evan T. Keller 3, Mengjie Chen 4,5 & Xiang Zhou 1,6 Differential expression (DE) analysis and gene set enrichment (GSE) analysis are commonly applied in single cell RNA sequencing (scRNA-seq) studies. Here, we develop an integrative 1234567890():,; and scalable computational method, iDEA, to perform joint DE and GSE analysis through a hierarchical Bayesian framework. By integrating DE and GSE analyses, iDEA can improve the power and consistency of DE analysis and the accuracy of GSE analysis. Importantly, iDEA uses only DE summary statistics as input, enabling effective data modeling through com- plementing and pairing with various existing DE methods. We illustrate the benefits of iDEA with extensive simulations. We also apply iDEA to analyze three scRNA-seq data sets, where iDEA achieves up to five-fold power gain over existing GSE methods and up to 64% power gain over existing DE methods. The power gain brought by iDEA allows us to identify many pathways that would not be identified by existing approaches in these data. 1 Department of Biostatistics, University of Michigan, Ann Arbor, MI 48109, USA. 2 School of Computer Science, Northwestern Polytechnical University, Xi’an, Shaanxi 710072, P.R. China. 3 Department of Urology, University of Michigan, Ann Arbor, MI 48109, USA. 4 Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA. 5 Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
    [Show full text]
  • Transcriptome-Wide Profiling of Cerebral Cavernous Malformations
    www.nature.com/scientificreports OPEN Transcriptome-wide Profling of Cerebral Cavernous Malformations Patients Reveal Important Long noncoding RNA molecular signatures Santhilal Subhash 2,8, Norman Kalmbach3, Florian Wegner4, Susanne Petri4, Torsten Glomb5, Oliver Dittrich-Breiholz5, Caiquan Huang1, Kiran Kumar Bali6, Wolfram S. Kunz7, Amir Samii1, Helmut Bertalanfy1, Chandrasekhar Kanduri2* & Souvik Kar1,8* Cerebral cavernous malformations (CCMs) are low-fow vascular malformations in the brain associated with recurrent hemorrhage and seizures. The current treatment of CCMs relies solely on surgical intervention. Henceforth, alternative non-invasive therapies are urgently needed to help prevent subsequent hemorrhagic episodes. Long non-coding RNAs (lncRNAs) belong to the class of non-coding RNAs and are known to regulate gene transcription and involved in chromatin remodeling via various mechanism. Despite accumulating evidence demonstrating the role of lncRNAs in cerebrovascular disorders, their identifcation in CCMs pathology remains unknown. The objective of the current study was to identify lncRNAs associated with CCMs pathogenesis using patient cohorts having 10 CCM patients and 4 controls from brain. Executing next generation sequencing, we performed whole transcriptome sequencing (RNA-seq) analysis and identifed 1,967 lncRNAs and 4,928 protein coding genes (PCGs) to be diferentially expressed in CCMs patients. Among these, we selected top 6 diferentially expressed lncRNAs each having signifcant correlative expression with more than 100 diferentially expressed PCGs. The diferential expression status of the top lncRNAs, SMIM25 and LBX2-AS1 in CCMs was further confrmed by qRT-PCR analysis. Additionally, gene set enrichment analysis of correlated PCGs revealed critical pathways related to vascular signaling and important biological processes relevant to CCMs pathophysiology.
    [Show full text]
  • Oncogenic Inhibition by a Deleted in Liver Cancer Gene Requires Cooperation Between Tensin Binding and Rho-Specific Gtpase-Activating Protein Activities
    Oncogenic inhibition by a deleted in liver cancer gene requires cooperation between tensin binding and Rho-specific GTPase-activating protein activities Xiaolan Qian*, Guorong Li*, Holly K. Asmussen*, Laura Asnaghi*, William C. Vass*, Richard Braverman*, Kenneth M. Yamada†, Nicholas C. Popescu‡, Alex G. Papageorge*, and Douglas R. Lowy*§ *Laboratory of Cellular Oncology and ‡Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; and †Laboratory of Cell and Developmental Biology, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892 Communicated by Ira Pastan, National Institutes of Health, Bethesda, MD, April 2, 2007 (received for review March 1, 2007) The three deleted in liver cancer genes (DLC1–3) encode Rho- The prototypic member, designated DLC1, is localized to GTPase-activating proteins (RhoGAPs) whose expression is fre- chromosome 8p21–22 in a region that is commonly deleted in quently down-regulated or silenced in a variety of human malig- hepatocellular carcinoma (5). Its expression is frequently down- nancies. The RhoGAP activity is required for full DLC-dependent regulated or silenced in various solid tumors and hematologic tumor suppressor activity. Here we report that DLC1 and DLC3 bind malignancies, predominantly by promoter methylation (6–13). to human tensin1 and its chicken homolog. The binding has been Ectopic reexpression in DLC1-deficient cancer cell lines can mapped to the tensin Src homology 2 (SH2) and phosphotyrosine suppress cell proliferation, induce apoptosis, and reduce tumor- binding (PTB) domains at the C terminus of tensin proteins. Distinct igenicity. The RhoGAP activity appears to be required for these DLC1 sequences are required for SH2 and PTB binding.
    [Show full text]
  • Impact of a Diet and Activity Health Promotion Intervention on Regional
    Hibler et al. Clinical Epigenetics (2019) 11:133 https://doi.org/10.1186/s13148-019-0707-0 RESEARCH Open Access Impact of a diet and activity health promotion intervention on regional patterns of DNA methylation Elizabeth Hibler1* , Lei Huang2, Jorge Andrade2,3 and Bonnie Spring1 Abstract Background: Studies demonstrate the impact of diet and physical activity on epigenetic biomarkers, specifically DNA methylation. However, no intervention studies have examined the combined impact of dietary and activity changes on the blood epigenome. The objective of this study was to examine the impact of the Make Better Choices 2 (MBC2) healthy diet and activity intervention on patterns of epigenome-wide DNA methylation. The MBC2 study was a 9-month randomized controlled trial among adults aged 18–65 with non-optimal levels of health behaviors. The study compared three 12-week interventions to (1) simultaneously increase exercise and fruit/ vegetable intake, while decreasing sedentary leisure screen time; (2) sequentially increase fruit/vegetable intake and decrease leisure screen time first, then increase exercise; (3) increase sleep and decrease stress (control). We collected blood samples at baseline, 3 and 9 months, and measured DNA methylation using the Illumina EPIC (850 k) BeadChip. We examined region-based differential methylation patterns using linear regression models with the false discovery rate of 0.05. We also conducted pathway analysis using gene ontology (GO), KEGG, and IPA canonical pathway databases. Results: We found no differences between the MBC2 population (n = 340) and the subsample with DNA methylation measured (n = 68) on baseline characteristics or the impact of the intervention on behavior change.
    [Show full text]
  • Transcriptomic and Proteomic Profiling Provides Insight Into
    BASIC RESEARCH www.jasn.org Transcriptomic and Proteomic Profiling Provides Insight into Mesangial Cell Function in IgA Nephropathy † † ‡ Peidi Liu,* Emelie Lassén,* Viji Nair, Celine C. Berthier, Miyuki Suguro, Carina Sihlbom,§ † | † Matthias Kretzler, Christer Betsholtz, ¶ Börje Haraldsson,* Wenjun Ju, Kerstin Ebefors,* and Jenny Nyström* *Department of Physiology, Institute of Neuroscience and Physiology, §Proteomics Core Facility at University of Gothenburg, University of Gothenburg, Gothenburg, Sweden; †Division of Nephrology, Department of Internal Medicine and Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan; ‡Division of Molecular Medicine, Aichi Cancer Center Research Institute, Nagoya, Japan; |Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden; and ¶Integrated Cardio Metabolic Centre, Karolinska Institutet Novum, Huddinge, Sweden ABSTRACT IgA nephropathy (IgAN), the most common GN worldwide, is characterized by circulating galactose-deficient IgA (gd-IgA) that forms immune complexes. The immune complexes are deposited in the glomerular mesangium, leading to inflammation and loss of renal function, but the complete pathophysiology of the disease is not understood. Using an integrated global transcriptomic and proteomic profiling approach, we investigated the role of the mesangium in the onset and progression of IgAN. Global gene expression was investigated by microarray analysis of the glomerular compartment of renal biopsy specimens from patients with IgAN (n=19) and controls (n=22). Using curated glomerular cell type–specific genes from the published literature, we found differential expression of a much higher percentage of mesangial cell–positive standard genes than podocyte-positive standard genes in IgAN. Principal coordinate analysis of expression data revealed clear separation of patient and control samples on the basis of mesangial but not podocyte cell–positive standard genes.
    [Show full text]